The present invention relates to derivatives of pyridino-pyridinones substituted (i) in position 3 with an imidazole, itself substituted with a group R1 and substituted (ii) in position 7 with an aryl or heteroaryl, itself substituted optimally with a motif of the type —[C(R3)(R4)]m—CO—N(R5)(R6), to the preparation thereof and to the application thereof in therapeutics as inhibitors of kinase activity of receptors for PDGF (platelet derived growth factors) ligands and optionally of receptors for the FLT3 (fms-like tyrosine kinase receptor) ligand.
The FLT3 and PDGF-R receptors are members of class III of the family of tyrosine kinase receptors (TKR), which also includes the stem cell factor receptor (c-kit) and M-CSF receptor (c-fms). They are characterized by an extracellular domain composed of 5 immunoglobulin-like domains containing the ligand binding region, a transmembrane domain, and an intracellular moiety composed of a juxtamembrane domain, a kinase domain split in two by an insert domain (split domain) (Ullrich & Schlessinger, 1990). The fixation of ligands on the TKR induces dimerization of the receptors, and activation of their tyrosine kinase moiety which leads to transphosphorylation of tyrosine residues (Weiss & Schlessinger, 1998). These phosphorylated residues thus serve as a point of anchorage for the intracellular signalling proteins which in fine cause various cellular responses: maintenance, division, proliferation, differentiation, or even cellular migration. (Claesson-Welsh, 1994).
The gene coding for FLT3 is located on chromosome 13q12 (Rosnet et al., 1992) and codes for the FLT3 protein (CD135 antigen) expressed specifically by the haematopoietic cells and more particularly the immature cells such as haematopoietic stem cells and myeloid and lymphoid multipotent progenitors and its expression disappears in the course of haematopoietic differentiation. Its ligand, the FLT3 Ligand, induces dimerization of the receptor, followed by autophosphorylation of the intracellular moiety of the receptor which leads to activation of the signalling cascade. The effects of activation of the receptor by its ligand are the survival and expansion of the multipotent progenitors.
Two isoforms of receptors to the PDGFs have been identified, the chain PDGF-Ralpha and the chain PDGF-Rbeta, which following fixation of their ligands are homo- or heterodimerized and induce intracellular signalling. The receptors to the PDGFs are essentially expressed by the cells of mesenchymatous origin and are notably found on fibroblasts, smooth muscle cells, pericytes and glial cells (Ross et al., 1986, Heldin, 1992).
Platelet Derived Growth Factor, PDGF, a protein with a molecular weight of about 30 000 dalton, is secreted essentially by the platelets, and secondarily by the endothelium, vascular smooth muscles and monocytes. It is formed from two polypeptide chains joined together by disulphide bridges forming either homodimers, or heterodimers. Four genes (7p22, 22q13, 4q31 and 11q22) have been described as coding for 4 different polypeptide chains (A, B, C and D), which once dimerized give five biologically active ligands PDGF-AA, BB, CC, DD and AB (for review, Yu et al., 2003). There is specificity of binding, including notably PDGF-AA for the alpha isoform of the receptor, PDGF-D for the BB form, and PDGF-C for the alpha and alpha/beta form. The PDGF ligands are potent mitogens, but are also involved in phenomena of migration, survival, apoptosis and cellular transformation.